Porphyromonas gingivalis is a well-established oral pathogen that produces substantial quantities of cysteine proteinase activity. These enzymes are essential for the growth and survival of P. gingivalis by providing a source of nutrients, interrupting host- defense mechanisms, and participating in the penetration and destruction of host connective tissue. The cysteine proteinases with specificity for arginine and lysine-containing peptide bonds (gingipain R and gingipain K, respectively) have the potential to contribute directly to the inflammatory disease process through direct complement activation, C5a generation, and bradykinin release. We have demonstrated that the generation of a systemic immune response to gingipain R1 or a peptide derived from the N- terminus of the catalytic domain is effective in limiting both colonization and invasion of P. gingivalis in the mouse chamber model. In this study, we will examine the ability of peptides derived from gingipain R1 to generate a protective response in the mouse periodontitis model and we will evaluate the feasibility of using avirulent Salmonella typhimurium strains expressing these peptides to stimulate mucosal and systemic immune responses and to protect against periodontal destruction in this model. In Aim 1, we will examine the immunogenic potential of peptides derived from the catalytic and adhesin domains of gingipain R1 in the mouse periodontitis model. In Aim 2, we will examine the systemic and mucosal immune responses in mice orally immunized with avirulent S. typhimurium expressing gingipain R1 derived peptides fused to protein carriers. Responses obtained following oral immunization will be compared to responses obtained in mice immunized systemically with S. typhimurium expressing the same gingipain R1 derived peptide fusions. In Aim 3, we will examine the protection against P. gingivalis infection in the mouse periodontitis model following immunization with S. typhimurium expressing gingipain RI derived peptide fusions. The results of these studies will enable us to demonstrate the feasibility of using attenuated Salmonella strains as carriers of gingipain R1 derived peptide fusions for subsequent evaluation of the role of the systemic and mucosal immune response against P. gingivalis induced periodontal destruction.